Venetoclax and Quizartinib in Treating Patients With FLT3-mutated Recurrent or Refractory Acute Myeloid Leukemia

NCT03735875 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2018-0608NCI-2018-02396
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib/II trial studies the side effects and best dose of venetoclax in combination with quizartinib and how well they work in treating patients with acute myeloid leukemia that has come back or does not respond to treatment, and who are FLT3-mutation positive. Venetoclax and quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Conditions

Acute Myeloid Leukemia With FLT3/ITD Mutation; Recurrent Acute Myeloid Leukemia; Refractory Acute Leukemia

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) as Determined by Dose Limiting Toxicity (Phase Ib)

  Up to 28 days

Secondary Outcomes (6)

• Duration of Response (DOR) (Phase Ib)

  Up to 4 years, 6 months

• Progression Free Survival (PFS) (Phase Ib)

  Up to 4 years, 6 months

• Event-free Survival (EFS) (Phase Ib)

  Up to 4 years, 6 months

• Overall Survival (OS) (Phase Ib)

  Up to 4 years, 6 months

• Number of Patients Bridged to Hematopoietic Stem Cell Transplant (HSCT) (Phase Ib)

  Up to 4 years, 6 months

Study Arms (2)

Phase I: Treatment (venetoclax, quizartinib)

EXPERIMENTAL

Dose finding: Patients receive quizartinib PO QD on days 1-28 and venetoclax PO QD beginning on day 8 of cycle 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 cycles at the discretion of the treating physician.

Drug: Quizartinib; Drug: Venetoclax

Phase II: Treatment (venetoclax, quizartinib)

EXPERIMENTAL

Patients will be treated at the established dose from the phase I portion of the study. Patients receive quizartinib PO QD on days 1-28 and venetoclax PO QD beginning on day 8 of cycle 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 cycles at the discretion of the treating physician.

Drug: Quizartinib; Drug: Venetoclax

Interventions

Quizartinib DRUG

Given PO

Also known as: AC-220, AC010220, AC220

Phase I: Treatment (venetoclax, quizartinib); Phase II: Treatment (venetoclax, quizartinib)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Phase I: Treatment (venetoclax, quizartinib); Phase II: Treatment (venetoclax, quizartinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• FLT3-ITD mutated patients with relapsed/refractory AML (up to four prior therapeutic regimens for AML i.e. up to salvage 4 AML), including patients who may have been previously exposed to prior FLT3-inhibitor/s other than quizartinib (stem cell transplant \[SCT\] or stem cell therapy for patients who previously underwent SCT/stem cell therapy in remission will not be considered a salvage regimen)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Serum direct bilirubin =\< 1.5 x upper limit normal (ULN) (or =\< 3.0 x ULN if deemed to be elevated due to leukemia)
• Alanine aminotransferase and/or aspartate aminotransferase (aspartate transaminase) =\< 2.5 x ULN (or =\< 5.0 x ULN if deemed elevated due to leukemia)
• Subjects with documented Gilbert's Syndrome may have a total bilirubin \> 1.5 x ULN
• Potassium levels should be within institutional normal limits
• Magnesium levels should be within institutional normal limits
• Calcium (normalized for albumin) levels should be within institutional normal limits
• Adequate renal function as demonstrated by a serum creatinine =\< 1.8
• Patients must provide written informed consent
• With the exception of patients with rapidly proliferative disease, the interval from prior treatment to time of initiation of venetoclax and quizartinib administration will be at least 14 days or at least 5 half-lives (whichever is shorter) for cytotoxic/noncytotoxic agents. The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochures, or drug-administration manuals) and will be documented in the protocol eligibility document. The use of chemotherapeutic or anti-leukemic agents is not permitted during the study with the following exceptions:
• Intrathecal (IT) therapy for patients with controlled central nervous system (CNS) leukemia at the discretion of the principal investigator (PI). Controlled CNS leukemia is defined by the absence of active clinical signs of CNS disease and no evidence of CNS leukemia on the most recent 2 simultaneous cerebrospinal fluid (CSF) evaluations
• Use of one dose of cytarabine (up to 2 g/m\^2) or hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and on therapy. These medications will be recorded in the case-report form
• Baseline ejection fraction by echocardiogram (ECHO) or multigated acquisition scan (MUGA) must be \>= 50%
• Women of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy

You may not qualify if:

• Subject has t(8;21) or inv(16) karyotype abnormalities
• Subject has acute promyelocytic leukemia (French-American-British Class M3 AML)
• Prior exposure to quizartinib at any time in the past
• Serum potassium \< 3.5 mEq/L despite supplementation, or \> 5.5 mEq/L. Serum magnesium above or below the institutional normal limit despite adequate management. Serum calcium (corrected for albumin levels) above or below institutional normal limit despite adequate management
• Patients with known allergy or hypersensitivity to quizartinib, venetoclax or any of their components
• Subject with a known history of being human immunodeficiency virus (HIV) positive (due to potential drug-drug interactions between antiretroviral medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections)
• Note: HIV testing is not required
• Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days prior to the initiation of study treatment
• Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator and/or the PI would adversely affect his/her participating in this study. Patients who have had any major surgical procedure within 14 days of day 1
• Subject has a malabsorption syndrome or other condition that precludes enteral route of administration
• Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: a. Uncontrolled systemic infection requiring intravenous (IV) therapy (viral, bacterial or fungal). Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable. Patients with neutropenic fever considered infection related should be afebrile for at least 72 hours prior to first dose
• Subject has a history of other malignancies within 1 year prior to study entry, with the exception of:
• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• M D Anderson Cancer Center

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

quizartinib; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Limitations and Caveats

This study was terminated early due to competing trials. All participants in the Phase I portion of this study were treated at dose level 0, therefore there was only one treatment arm for this study. This study did not move on to the Phase II portion of the study. Therefore, no patients were accrued on the Phase II portion of the study.

Results Point of Contact

• Title: Naval Daver, MD./Professor
• Organization: The University of Texas MD Anderson Cancer Center

NDaver@mdanderson.org

713-794-4392

Study Officials

• Naval G Daver

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2018
• First Posted: November 8, 2018
• Study Start: January 25, 2019
• Primary Completion: July 26, 2023
• Study Completion: July 26, 2023
• Last Updated: September 19, 2024
• Results First Posted: September 19, 2024

Record last verified: 2024-08

Locations

US (1)